Submissions for variant NM_000441.2(SLC26A4):c.84C>A (p.Ser28Arg)

gnomAD frequency: 0.00001  dbSNP: rs539699299

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169378	SCV000220764	likely pathogenic	Pendred syndrome	2014-10-02	criteria provided, single submitter	literature only
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000505875	SCV000605155	pathogenic	not provided	2017-05-19	criteria provided, single submitter	clinical testing	The c.84C>A variant (rs539699299) has been observed as a homozygote (Park 2003) or in trans with a pathogenic variant (Ladsous 2014) in patients with a clinical diagnosis of Pendred syndrome (PS). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.003% (identified in 1 out of 30,956 chromosomes). Additionally, a different nucleic acid change leading to the same amino acid substitution (c.82A>C; p.Ser28Arg) a different variant in same codon (c.82A>G; p.Ser28Gly) have also been identified in patients with enlarged vestibular aqueduct (EVA; Park 2005 and Okamoto 2014, respectively). Analysis of the p.Ser28Arg variant in heterologous cell culture has revealed this substitution results in defects in ion flux compared to wild-type SLC26A4 protein (Dossena 2006a, Dossena 2006b, Yoon 2008). This variant is also listed in the ClinVar database as likely pathogenic (Variation ID: 188998). Therefore, the c.84C>A variant satisfies our criteria for classification as pathogenic.
Invitae	RCV000505875	SCV000941761	pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 28 of the SLC26A4 protein (p.Ser28Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Pendred syndrome (PMID: 11919333, 15679828, 16570074, 24224479, 29739340). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188998). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 16791000, 18310264). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Human Genetics, Institute of Biosciences - University of Sao Paulo	RCV001580204	SCV001809838	pathogenic	Autosomal recessive nonsyndromic hearing loss 4		criteria provided, single submitter	research
Genome-Nilou Lab	RCV001580204	SCV002027650	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2021-09-05	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169378	SCV002027661	likely pathogenic	Pendred syndrome	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001580204	SCV004201856	pathogenic	Autosomal recessive nonsyndromic hearing loss 4	2024-01-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169378	SCV002079959	pathogenic	Pendred syndrome	2021-02-12	no assertion criteria provided	clinical testing